Unexplained Infertility

What is unexplained infertility?

Unexplained infertility is a type of infertility where the cause for not conceiving is unknown. The diagnosis is given to couples who have tried to conceive for one year (female age < 35 years) or 6 months (female age > 35 years).

What causes unexplained infertility?

There is speculation that female gametes, male gametes, abnormal uterine implantation, or some combination of these elements hold the key to explaining the low rate of pregnancy success in patients who receive this diagnosis. Currently, there are no tests to prove this theory. Patients diagnosed with unexplained infertility have an untreated fecundity rate of 2% to 4% per menstrual cycle, which is significantly lower than normal fertile couples whose cycle fecundity rate is 20% to 25% during the first few months of attempting pregnancy.

How is unexplained infertility diagnosed?

The diagnosis is one of exclusion, where ovulatory function, uterine cavity, fallopian tubes, and semen analysis are normal.

How is unexplained infertility treated?

Treatments for this condition are experimental, as the underlying cause of unexplained infertility is not well defined.

  • Intrauterine insemination (IUI) in natural cycles (release of 1 egg per cycle): Intrauterine insemination, where the sperm is placed into the uterus during a woman’s fertile window, in natural cycles, only marginally increases the pregnancy rate (5%) in couples with this diagnosis. Therefore, IUI is not recommended without fertility drugs to stimulate the ovaries to treat this condition.
  • Ovarian stimulation with clomiphene citrate or gonadotropins (protein hormones secreted by the pituitary gland that prompt the ovary to release > 1 egg per cycle) without or with IUI: Ovarian stimulation facilitates the maturation and release of multiple eggs into the fallopian tube, where fertilization will occur. Without accompanying IUI, clomiphene citrate-induced ovarian stimulation does not improve results compared to expectant management (timing intercourse to the ovulation cycle). Superovulation using gonadotropins without IUI has a slightly higher success rate per treatment cycle (5% to 7%) compared to no intervention (2% to 4%). In contrast, pregnancy success will moderately increase using either drug treatment in conjunction with IUI: clomiphene citrate + IUI (5% to 10%); gonadotropins + IUI(7% to 20%), when compared to controls. The main risk of superovulation treatment is multiple gestation (conception of twins, triplets, or other higher order multiples) at around 8% for clomiphene citrate and between 14% to 39% with gonadotropins. Many clinicians recommend up to 4 to 6 treatment cycles with either clomiphene citrate or gonadotropins. Other clinicians prescribe letrazol, an aromatase inhibitor, which acts in a manner similar to clomiphene. This drug may produce better results due to the medication’s shorter half life. Experts do not agree on whether one or two inseminations should be performed per treatment cycle. Several studies suggest that there is no improvement in treatment outcome when a second intrauterine insemination is performed.
  • Assisted reproductive technologies: In vitro fertilization (IVF) results have been shown to achieve a clinical pregnancy rate per cycle of 50%, compared to 11% for couples using expectant management. The IVF overall live birth rate in a 2007 national registry was 31.8% per attempt. It is of note that intracytoplasmic sperm injection (ICSI) where a single sperm is injected directly into an egg, does not significantly improve the IVF success rate in couples diagnosed with unexplained infertility.

Consensus on treatment and procedures for women over 39 is not clear; many clinicians recommend moving directly to in vitro fertilization, as egg quality rapidly deteriorates in women as they enter their forties. Further complexity is added to clinical strategy when the couples diagnosed with unexplained infertility would like to have more than one child. For example, a 38 year-old woman, who wants to have two children, might be well served with conventional treatment (superovulation and intrauterine insemination) to achieve a single pregnancy. However it might be problematic to conceive two children this way, as conceiving immediately after giving birth is not recommended, but waiting may compromise a second pregnancy success due to advanced maternal age.

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